Multiple sclerosis (MS) is a chronic autoimmune disease characterized by degradation of the CNS myelin. Etiology of the disease is still unknown; however, oligodendrocyte apoptosis may represent an initiating event. Defects in the regulation of the removal of apoptotic cell bodies and degraded myelin can fuel the immune response and, thus, contribute to disease development and/or progression. Low density lipoprotein receptor-related protein-1 (LRP1) is a cellular receptor which functions in endocytosis and cell signaling. We have demonstrated that LRP1 is a key endocytic receptor for myelin in vitro. In addition, LRP1 levels are increased in the brains and spinal cords of mice subjected to a model of MS, EAE. We hypothesize that LRP1 could be directly involved in the regulation of MS by mediating degraded myelin and apoptotic cell removal. We will test this hypothesis by a combination of in vivo and in vitro experiments. As complete LRP1 deficiency is lethal, the role of LRP1 in the EAE model will be determined using mice with the conditional LRP1 deficiency in myeloid cells. Using this model, we demonstrate in preliminary experiments that LRP1 deficiency leads to a significant increase in EAE symptoms, suggesting that LRP1 function in myeloid cells inhibits disease. Effector functions of LRP1-deficient macrophages and microglia will be characterized. Finally, we propose to identify LRP1 ligands in myelin preparations, using a proteomics discovery approach. This research grant proposal should provide the basis for understanding the function of LRP1 in MS and for the potential development of novel therapeutics for MS patients.